AIP1 Recruits Phosphatase PP2A to ASK1 in Tumor Necrosis Factor–Induced ASK1-JNK Activation

Wang, Min; Lin, Yan; Tang, Shibo; Yu, Luyang; Zhang, Haifeng; Wan, Ting; Luhn, Tricia; Fu, Haian; Chen, Hong

doi:10.1161/circresaha.107.168153

Cited by 74 publications

(72 citation statements)

References 38 publications

(62 reference statements)

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“…Based on these observations, it is tempting to speculate that the interaction between PP2A to IKKβ requires an adaptor protein that is only made and thus available after stimulation. Recently, a similar case has been reported that AIP1 [apoptosis signal-regulating kinase 1(ASK1)-interacting protein 1] recruits PP2A to ASK1 after TNF treatment (26). Alternatively, PP2A may undergo a modification that is necessary to interact with IKK.…”

Section: Discussionmentioning

confidence: 87%

Interleukin-23 production in dendritic cells is negatively regulated by protein phosphatase 2A

Chang

Voorhees

Liu

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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IL-12 and IL-23 are produced by activated antigen-presenting cells but the two induce distinct immune responses by promoting Th1 and Th17 cell differentiation, respectively. IL-23 is a heterodimeric cytokine consisting of two subunits: p40 that is shared with IL-12 and p19 unique to IL-23. In this study, we showed that the production of IL-23 but not IL-12 was negatively regulated by protein phosphatase 2A (PP2A) in dendritic cells (DC). PP2A inhibits IL-23 production by suppressing the expression of the IL-23p19 gene. Treating DC with okadaic acid that inhibits the PP2A activity or knocking down the catalytic subunit of PP2A with siRNA enhanced IL-23 but not IL-12 production. Unlike PP2A, MAP kinase phosphatase-1 or CYLD did not show an effect on IL-23 production supporting the specificity of PP2A. PP2A-mediated inhibition requires a newly made protein that is likely responsible for bringing PP2A and IKKβ together upon LPS stimulation, which then results in the termination of IKK phosphorylation. Thus, our results uncovered an important role of the protein phosphatase in the regulation of IL-23 production and identified PP2A as a previously uncharacterized inhibitor of IL-23p19 expression in DC.cytokine | NF-κB | TLR

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Section: Discussionmentioning

confidence: 87%

Interleukin-23 production in dendritic cells is negatively regulated by protein phosphatase 2A

Chang

Voorhees

Liu

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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“…DAB2IP then displaces the inhibitory binding between ASK1 and 14-3-3 protein, favoring ASK1 activation. 40 DAB2IP also mediates recruitment of PP2A to ASK1, binding both proteins through its C2 domain; this favors removal of the inhibitory S967 phosphorylation and further activation of ASK1 87 Tumor suppressor DAB2IP in cancer A Bellazzo et al expression of HIF-2α in renal cell carcinoma cells. 49 Therefore, DAB2IP inactivation may promote an hypoxia-like response, with upregulation of HIF target genes and increased expression and activity of VEGF proteins, affecting the cancer cell and its microenvironment, and promoting tumor vascularization.…”

Section: Dab2ip Inactivation Fosters Tumor Progressionmentioning

confidence: 99%

Block one, unleash a hundred. Mechanisms of DAB2IP inactivation in cancer

2016

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One of the most defining features of cancer is aberrant cell communication; therefore, a molecular understanding of the intricate network established among tumor cells and their microenvironment could significantly improve comprehension and clinical management of cancer. The tumor suppressor DAB2IP (Disabled homolog 2 interacting protein), also known as AIP1 (ASK1 interacting protein), has an important role in this context, as it modulates signal transduction by multiple inflammatory cytokines and growth factors. DAB2IP is a Ras-GAP, and negatively controls Ras-dependent mitogenic signals. In addition, acting as a signaling adaptor, DAB2IP modulates other key oncogenic pathways, including TNFα/NF-κB, WNT/β-catenin, PI3K/AKT, and androgen receptors. Therefore, DAB2IP inactivation can provide a selective advantage to tumors initiated by a variety of driver mutations. In line with this role, DAB2IP expression is frequently impaired by methylation in cancer. Interestingly, recent studies reveal that tumor cells can employ other sophisticated mechanisms to disable DAB2IP at the post-transcriptional level. We review the mechanisms and consequences of DAB2IP inactivation in cancer, with the purpose to support and improve research aimed to counteract such mechanisms. We suggest that DAB2IP reactivation in cancer cells could be a strategy to coordinately dampen multiple oncogenic pathways, potentially limiting progression of a wide spectrum of tumors.

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“…Serine/threonine protein phosphatase type 5 (PP5) and PP2C dephosphorylate phosphorylated (p)-Thr-838, 28,32 whereas PP2A and SHP2 dephosphorylate p-Ser-967 and p-Tyr-718, respectively. 31,33 Little is known about the kinase or phosphatase that regulates phosphorylation at Ser-1034. Although ASK1 phosphorylation is known to be involved in the regulation of apoptosis, only a few reports show that ASK1 phosphorylation or activity is dependent on the cell cycle.…”

mentioning

confidence: 99%

Cell cycle-dependent Cdc25C phosphatase determines cell survival by regulating apoptosis signal-regulating kinase 1

Cho

Park

et al. 2015

Cell Death Differ

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Cdc25C (cell division cycle 25C) phosphatase triggers entry into mitosis in the cell cycle by dephosphorylating cyclin B-Cdk1. Cdc25C exhibits basal phosphatase activity during interphase and then becomes activated at the G 2 /M transition after hyperphosphorylation on multiple sites and dissociation from 14-3-3. Although the role of Cdc25C in mitosis has been extensively studied, its function in interphase remains elusive. Here, we show that during interphase Cdc25C suppresses apoptosis signal-regulating kinase 1 (ASK1), a member of mitogen-activated protein (MAP) kinase kinase kinase family that mediates apoptosis. Cdc25C phosphatase dephosphorylates phospho-Thr-838 in the activation loop of ASK1 in vitro and in interphase cells. In addition, knockdown of Cdc25C increases the activity of ASK1 and ASK1 downstream targets in interphase cells, and overexpression of Cdc25C inhibits ASK1-mediated apoptosis, suggesting that Cdc25C binds to and negatively regulates ASK1. Furthermore, we showed that ASK1 kinase activity correlated with Cdc25C activation during mitotic arrest and enhanced ASK1 activity in the presence of activated Cdc25C resulted from the weak association between ASK1 and Cdc25C. In cells synchronized in mitosis following nocodazole treatment, phosphorylation of Thr-838 in the activation loop of ASK1 increased. Compared with hypophosphorylated Cdc25C, which exhibited basal phosphatase activity in interphase, hyperphosphorylated Cdc25C exhibited enhanced phosphatase activity during mitotic arrest, but had significantly reduced affinity to ASK1, suggesting that enhanced ASK1 activity in mitosis was due to reduced binding of hyperphosphorylated Cdc25C to ASK1. These findings suggest that Cdc25C negatively regulates proapoptotic ASK1 in a cell cycle-dependent manner and may play a role in G 2 /M checkpointmediated apoptosis.

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AIP1 Recruits Phosphatase PP2A to ASK1 in Tumor Necrosis Factor–Induced ASK1-JNK Activation

Cited by 74 publications

References 38 publications

Interleukin-23 production in dendritic cells is negatively regulated by protein phosphatase 2A

Interleukin-23 production in dendritic cells is negatively regulated by protein phosphatase 2A

Block one, unleash a hundred. Mechanisms of DAB2IP inactivation in cancer

Cell cycle-dependent Cdc25C phosphatase determines cell survival by regulating apoptosis signal-regulating kinase 1

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